Kidney dialysis machines have been successfully used for the past 30 years to aid patients suffering from various forms of kidney disease. The machines are used with a cartridge, known in the art as a "dialyzer" or "artificial kidney", which contains a semipermeable membrane. The membrane divides the dialyzer into a blood compartment and a dialysate compartment. In broad outline, as the patient's blood passes through the blood compartment, waste products move across the membrane into the dialysate compartment, while high molecular weight blood components are retained in the blood compartment.
The structure of a typical dialyzer 13 employing hollow fibers 11 as the semipermeable membrane is shown in FIG. 1. The blood compartment of the dialyzer comprises the space inside of fibers 11 while dialysate compartment comprises the space outside the fibers. To form these compartments, fibers 11 are embedded in potting compound 15, 17 at their ends. The patient's blood passes through the dialyzer by means of entrance port 19 and exit port 21, while dialysate enters and leaves by ports 23 and 25, respectively.
When initially introduced, dialyzers were one use devices. With time, however, efforts were made to reprocess dialyzers to reduce the overall cost to the patient and the health care delivery system. The cost benefits achieved by reprocessing are significant. For example, a new dialyzer typically costs around $30. With reprocessing, a dialyzer can be used between 5 and 20 times without substantial lost of efficacy. The cost of reprocessing is approximately $4 per unit. Accordingly, by employing reprocessing, the dialyzer cost per treatment is conservatively less than about $10, as opposed to $30 if a new dialyzer were used for each treatment.
Since a typical patient receives approximately 150 treatments per year and since in the United States alone approximately 120,000 patients are on hemodialysis, the cost savings achieved by reprocessing are enormous. For example, based on the $30 to $10 differential discussed above, the savings would amount to 360 million dollars per year if reprocessing were used for all U.S. patients. At present, approximately 75% of the treatments performed in the United States employ reprocessed dialyzers.
In overview, reprocessing of dialyzers involves three basic steps: 1) cleansing, 2) efficacy confirmation, and 3) disinfection.
The cleansing of a dialyzer involves removing residual blood and organic material from the blood side and removing dialysate from the dialysate side of the semipermeable membrane. Equipment specifically designed to perform this step is commercially available. Such equipment causes cleansing solution to pass through the walls of the hollow fibers making up the dialyzer so as to remove undesired material from both the blood and dialysate compartments. A number of cleansing solutions for use in this step are known, including solutions composed of purified water and bleach, a peracetic acid mixture, hydrogen peroxide, or other cleansing agents. Purified water by itself has also been used for cleansing.
The efficacy confirmation step involves determining 1) that the membrane and associated structural components of a cleansed dialyzer still maintain a barrier between the blood and dialysate compartments, and 2) that the cleansed dialyzer has a membrane area substantially equivalent to a new dialyzer. This step is typically performed by measuring the volume of the blood compartment.
The disinfection step involves killing microorganisms which may have contaminated the blood or dialysate compartments during or after use. Again, equipment specifically designed to perform this step is commercially available and in many cases, the same piece of equipment performs the cleansing, testing, and disinfection functions.
Of these three steps, disinfection has proven to be most difficult, both because it must be highly effective if reprocessed dialyzers are to be safe and because the critical properties of the dialyzer's semipermeable membrane must remain substantially unchanged by the disinfection process. Also, the semipermeable membranes used in dialyzers have large areas, high porosities, and, after use, are coated with proteins and other organic materials. As a result, the membrane of a used dialyzer is highly susceptible to microbial growth and effective killing of microorganisms on such a membrane, without damaging the membrane, is difficult to accomplish.
Prior to the present invention, two basic types of disinfection have been employed in the art. See Deane et al., "Multiple Use of Hemodialyzers," In: Replacement of Renal Function by Dialysis, 3rd edition, edited by JF Maher, Kluwer Academic Publishers, Boston, Mass. 1989, pages 400-416.
The most common approach uses a disinfecting solution containing a toxic chemical such as formaldehyde, glutaraldehyde, or a mixture of peracetic acid, hydrogen peroxide, and acetic acid. See, for example, AAMI Recommended Practice for Reprocessing Hemodialyzers, Association for the Advancement of Medical Instrumentation, Arlington, Va., 1993. Because of the toxicity of these disinfecting chemicals, this approach suffers from the problem of ensuring that all of the disinfecting solution is removed from the dialyzer prior to reuse. Also, disinfecting solutions based on a peracetic acid mixture raise concerns regarding the solution's efficacy in view of its limited shelf life and inactivation by organic material. Further, the use of formaldehyde raises environmental concerns in view of the known carcinogenic effects of this compound.
In connection with these prior disinfecting solutions, it should be noted that in practice, only high level disinfection and not sterilization has been achieved, that is, although the solutions have killed all pathogenic organisms, they have not made the reprocessed dialyzers free of all microbial viability. In contrast, as discussed in detail below, the present invention achieves sterilization of the dialyzer.
A second approach to disinfection involves heat treating the dialyzer at a temperature above 100.degree. C. for approximately 20 hours. See Kaufman et al., "Clinical Experience with Heat Sterilization for Reprocessing Dialyzers," ASAIO Transactions, Vol. 38, No. 3, July-September 1992, pages M338-M340. Although this approach has been found to work successfully in practice and avoids the toxicity problem associated with disinfecting solutions of the type discussed above, it too suffers from problems. In particular, it can only be used with dialyzers which can withstand the high temperatures and long processing times at such temperatures required by the procedure. Also, even for dialysis membranes which can withstand these processing conditions, a high rate of failure of the structural components of the dialyzer, e.g., the potting material for the hollow fibers, has been observed. This failure rate limits the number of reuses of the dialyzer to approximately 10 times.
The use of citric acid in connection with the cleansing of dialysis machines has been disclosed in a number of patent publications. In particular, Tell et al., U.S. Pat. No. 4,690,772, discloses a sterilant comprising sodium chlorite, citric acid, and a sodium bicarbonate buffer. Sodium chlorite is toxic and thus this sterilant falls into the chemical disinfection category discussed above.
EPO Patent Publication No. 393,386 discloses the use of a citric acid solution to clean a dialysis machine after bicarbonate dialysis, specifically, to decalcify the machine. Similarly, EPO Patent Publication No. 505,763 discloses the use of citric acid solutions to disinfect dialysis machines. In particular, this publication states that such a solution can be applied to the machine's water-circuit. A water-circuit is used in a dialysis machine to form the dialysate from a chemical concentrate. It is not part of the dialyzer.
Although these references do mention the use of citric acid in connection with dialysis machines, none of them discloses or suggests that citric acid can be used to disinfect a dialyzer. As discussed in detail below, in accordance with the invention, it has been surprisingly found that dialyzers not only can be disinfected but can be sterilized at temperatures below 100.degree. C. by means of a citric acid solution provided that the dialyzer's semipermeable membrane is exposed to the citric acid solution for a sufficient period of time, i.e., at least about 15 hours. Such exposure has been found to leave both the permeability of the membrane and the integrity of the dialyzer essentially unchanged.